Salt of pyranose-substituted heterocyclic compound, preparation method therefor and use thereof
11155571 · 2021-10-26
Assignee
- Yabao Pharmaceutical Group Co., Ltd. (Shanxi, CN)
- Suzhou Yabao Pharmaceutical R&D Co., Ltd. (Jiangsu, CN)
Inventors
Cpc classification
C07H19/23
CHEMISTRY; METALLURGY
C07H1/00
CHEMISTRY; METALLURGY
C07H19/04
CHEMISTRY; METALLURGY
International classification
C07H19/23
CHEMISTRY; METALLURGY
Abstract
The present application relates to a salt of a pyranose-substituted heterocyclic compound, a preparation method therefor, and use thereof, and in particular, to an acid addition salt of a compound of formula (I) or a prodrug thereof, and further relates to D-glucuronate of a crystalline compound of formula (I) or a prodrug thereof. D-glucuronate of a crystalline compound of formula (II) has particular advantages in terms of crystallizability, subsequent purification, stability, formulation medicinal properties or quality control, and is most applicable for improving the formulation pharmaceutical properties, purity and quality control, as well as large-scale process development of such drugs.
Claims
1. An acid addition salt of a compound represented by formula (I) or a prodrug thereof: ##STR00005## wherein R.sub.1, R.sub.2 and R.sub.6 are the same or different from each other, and independently selected from C.sub.1-C.sub.8 alkyl which is unsubstituted or optionally substituted with one or more R.sub.a; R.sub.3 and R.sub.5 are the same or different from each other, and independently selected from —(CH.sub.2).sub.n— which is unsubstituted or optionally substituted with one or more R.sub.b; R.sub.4 is selected from C.sub.6-C.sub.20 aryl which is unsubstituted or optionally substituted with one or more R.sub.c; R.sub.a, R.sub.b and R.sub.c are the same or different from each other, and independently selected from the group consisting of halogen, hydroxyl, mercapto, nitro and amino; n is an integer of 1 to 8; the acid addition salt is D-glucuronate; and the prodrug is an ester formed by a hydroxyl group of the compound represented by formula (I) with a first acid.
2. The acid addition salt according to claim 1, wherein: R.sub.1 is selected from the group consisting of —CH.sub.3, —CH.sub.2CH.sub.3, —CH.sub.2Cl, —CH.sub.2F, —CH.sub.2OH and —CH.sub.2SH; R.sub.2 is selected from the group consisting of —CH.sub.3, —CH.sub.2CH.sub.3 and —CH.sub.2CH.sub.2CH.sub.3; R.sub.3 is selected from the group consisting of —CH.sub.2—, —(CH.sub.2).sub.2— and —(CH.sub.2).sub.3—; R.sub.4 is Ph-; R.sub.5 is selected from the group consisting of —CH.sub.2—, —(CH.sub.2).sub.2— and —(CH.sub.2).sub.3—; R.sub.6 is selected from the group consisting of —CH.sub.3, —CH.sub.2CH.sub.3, —CH.sub.2CH.sub.2CH.sub.3, —CH(CH.sub.3).sub.2, —CH(CH.sub.3)CH.sub.2CH.sub.3 and —CH.sub.2CH(CH.sub.3).sub.2.
3. A method for preparing the acid addition salt according to claim 1, comprising reacting the compound represented by formula (I) or the prodrug thereof with D-glucuronic acid.
4. The method for preparing the acid addition salt according to claim 3, wherein the reaction is carried out in the presence of a solvent.
5. The method for preparing the acid addition salt according to claim 3, wherein a molar ratio of the compound represented by formula (I) or the prodrug thereof to the acid is greater than or equal to 1:1.
6. The method for preparing the acid addition salt according to claim 3, wherein the reaction is carried out at a temperature in the range of 0-30° C.
7. A crystal form of the acid addition salt or a prodrug thereof according to claim 1.
8. The crystal form according to claim 7, wherein the crystal form is one or more selected from the group consisting of: (1) a crystal form A of D-glucuronate of the compound represented by formula (II), having one or more characteristic peaks at 4.3±0.2°, 9.2±0.2°, 12.7±0.2°, 13.9±0.2°, 16.9±0.2° and 21.9±0.2° represented by 2θ angle in an X-ray powder diffraction pattern, wherein the compound represented by formula (II) has a structure of: ##STR00006## (2) a crystal form D of D-glucuronate of the compound represented by formula (II), having one or more characteristic peaks at 8.5±0.2°, 11.8±0.2°, 18.6±0.2°, and 21.5±0.2° represented by 2θ angle in an X-ray powder diffraction pattern; (3) a crystal form C of D-glucuronate of the compound represented by formula (II), having an X-ray powder diffraction pattern substantially same as shown in a pattern of a crystal form C in
9. A method for preparing the crystal form according to claim 8, wherein (1) when the crystal form comprises the crystal form A, the method comprises reacting the compound represented by formula (II) with D-glucuronic acid in a mixed solvent of tetrahydrofuran and water, and drying after completion of the reaction to obtain the crystal form A; (2) when the crystal form comprises the crystal form D, the method comprises stirring the crystal form A of D-glucuronate of the compound represented by formula (II) in 2-butanone, 1,4-dioxane or a mixture thereof, separating a solid, and drying to obtain the crystal form D; (3) when the crystal form comprises the crystal form C, the method comprises suspending and stirring the crystal form A of D-glucuronate of the compound represented by the formula (II) in isopropanol, separating a solid, and drying to obtain the crystal form C; (4) when the crystal form comprises the crystal form E, the method comprises suspending and stirring the crystal form A of D-glucuronate of the compound represented by the formula (II) in toluene, separating a solid, and drying to obtain the crystal form E; and (5) when the crystal form comprises the crystal form F, the method comprises suspending and stirring the crystal form A of D-glucuronate of the compound represented by the formula (II) in dichloromethane, separating a solid, and drying to obtain the crystal form F.
10. A pharmaceutical composition comprising the acid addition salt according to claim 1, and/or the crystal form of the acid addition salt according to claim 1, and a pharmaceutically acceptable excipient.
11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a formulation that can be administered orally, parenterally, transmucosally, nasally, topically, or sublingually.
12. A method for treating diseases, comprising administering a therapeutically effective amount of the acid addition salt according to claim 1, the crystal form of the acid addition salt according to claim 1, or the pharmaceutical composition comprising the acid addition salt according to claim 1 and/or the crystal form of the acid addition salt according to claim 1 to a patient in need thereof; wherein the diseases include diseases or disorders mediated by SGLT-1 and/or SGLT-2.
13. The acid addition salt according to claim 2, wherein a molar ratio of the compound represented by formula (I) to D-glucuronic acid that forms the acid addition salt is 1:1.
14. The acid addition salt according to claim 2, wherein the compound represented by formula (I) has a structure represented by formula (II): ##STR00007##
15. The method for preparing the acid addition salt according to claim 4, wherein the solvent is selected from the group consisting of alcohols solvent, ketones solvent, ethers solvent and esters solvent, or any combination thereof.
16. The method for preparing the acid addition salt according to claim 4, wherein the alcohols solvent is selected from the group consisting of methanol, ethanol, isopropanol, butanol, pentanol, decanol, n-dodecyl alcohol, cyclopentanol, cyclohexanol, benzyl alcohol, and phenylethanol, or any combination thereof the ketones solvent is selected from the group consisting of acetone, 2-butanone, methyl isopropyl ketone, methyl cyclohexanone, cyclohexanone, and methyl isobutyl ketone, or any combination thereof; the ethers solvent is selected from the group consisting of diethyl ether, methyl ethyl ether, methyl tert-butyl ether, dipropyl ether, dibutyl ether, 1,4-dioxane, and tetrahydrofuran, or any combination thereof; and the esters solvent is selected from the group consisting of ethyl acetate, hexyl acetate, methyl acetate, and isopropyl acetate, or any combination thereof.
17. The crystal form according to claim 7, wherein the crystal form is a crystal form of D-glucuronate of the compound represented by formula (I) or formula (II) or the prodrug thereof, wherein the compound represented by Formula II has a structure of: ##STR00008##
18. The method according to claim 12, wherein the diseases or disorders mediated by SGLT-1 and/or SGLT-2 include hyperglycemia-related disease, impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or metabolic syndrome.
19. The method according to claim 18, wherein the hyperglycemia-related disease is diabetes.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1) In order to describe the examples of the present application and the technical solutions of the prior art more clearly, the drawings required in the examples and the prior art are briefly introduced below. Obviously, the drawings described as below are only some examples of the present application, for those ordinary skilled in the art, other drawings can be also obtained based on these drawings without creative efforts.
(2)
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DETAILED DESCRIPTION OF THE INVENTION
(7) The technical solutions of the present application will be further described in detail below with reference to exemplary examples. It should be understood that the following examples are only illustrative for describing and explaining the present application, which should not be interpreted as limiting the scope of protection of the present application. The technical solutions implemented based on the above contents of the present application are all covered by the scope of protection of the present application.
(8) Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available, or can be prepared by known methods.
(9) Instruments and Test Methods
(10) XRPD patterns were collected on PANalytacal XPERT-3 and Bruker D2 X-ray powder diffraction analyzers. X-ray: Cu, Kα, Kα1 (Å): 1.540598; Kα2 (Å): 1.544426; intensity ratio of Kα2/K═1:0.50; scan range: 3°-40°.
(11) TGA and DSC spectrums were collected on TA Q500/5000 thermogravimetric analyzer and TAQ200/2000 differential scanning calorimeter, respectively.
Preparation Example 1: Preparation of the Compound Represented by Formula (II)
(12) According to the method described in Example 1b of Chinese invention patent application CN201480054233.8, the compound represented by formula (II) was prepared, and the X-ray powder diffraction pattern showed that it was an amorphous product, and the purity was 97.12%. Unless otherwise stated, the amorphous product obtained in this preparation example was used as the raw material of the compound represented by formula (II) in the following examples.
Example 1: Preparation of D-Glucuronate of the Compound Represented by Formula (II)
(13) About 250 mg of the compound of formula (II) and 1.1 equivalent of D-glucuronic acid (molar ratio of 1:1.1) were weighed and added into 10 mL of acetone, and stirred at about 50-60° C. After the reaction was completed, the mixture was filtered and dried to obtain the D-glucuronate of the compound represented by formula (II). Its mass spectrum data: MS (m/z): 750.5 (M+H); MS (m/z): 193.1 (glucuronic acid-H). After analysis, it was confirmed that the compound obtained is D-glucuronate of the compound of formula (II).
Example 2: Preparation of Crystal form A of D-Glucuronate of the Compound Represented by Formula (II)
(14) The compound represented by formula (II) (3 g), D-glucuronic acid (0.78 g), and 30 mL tetrahydrofuran (containing 5% water by mass) were sequentially added into a 50 mL single-necked bottle, stirred at room temperature for 24 h, and filtered to obtain a solid. The solid was rinsed with 10 mL of tetrahydrofuran, dried under vacuum at 35-40° C. for 2-3 h, and weighed to obtain 4 g of product (moisture 0.15%, THF 5.81%). The X-ray powder diffraction pattern thereof is shown in
Example 3: Preparation of Crystal Form A of D-Glucuronate of the Compound Represented by Formula (II)
(15) The compound represented by formula (II) (250.1 mg) and D-glucuronic acid (66.3 mg) were weighed and added into a 5 mL glass bottle. 2 mL of tetrahydrofuran/water (v:v, 19:1) was added, and the mixture was stirred at 1000 rpm for 7 days. The mixture was centrifuged to obtain a solid. The solid was dried under vacuum at room temperature for 2 h. According to the X-ray powder diffraction pattern, it is confirmed that the crystal form A was obtained.
Example 4: Preparation of Crystal Form C of D-Glucuronate of the Compound Represented by Formula (II)
(16) 100 mg of the crystal form A prepared in Example 2 was weighed and added into a 2 mL glass bottle. 0.5 mL of isopropanol was added, and the mixture was suspended and stirred overnight. The mixture was centrifuged to obtain a solid. The solid was dried under vacuum at room temperature for 2 h. According to the X-ray powder diffraction pattern shown in
Example 5: Preparation of Crystal Form D of D-Glucuronate of the Compound Represented by Formula (II)
(17) 1.5 g of the crystal form A was weighed and added into 15 ml of 2-butanone. The mixture was slurried at room temperature for 4-5 h, filtered, and dried under vacuum at 35-40° C. for 2-3 h. According to the X-ray powder diffraction pattern shown in
Example 6: Preparation of Crystal Form D of D-Glucuronate of the Compound Represented by Formula (II)
(18) 100 mg of the crystal form A prepared in Example 2 was weighed and added into a 2 mL glass bottle. 0.5 mL of 2-butanone was added, and the mixture was suspended and stirred overnight. The mixture was centrifuged to obtain a solid. The solid was dried under vacuum at room temperature for 2 h. According to the X-ray powder diffraction pattern, it is confirmed that the crystal form D was obtained.
Example 7: Preparation of Crystal Form D of D-Glucuronate of the Compound Represented by Formula (II)
(19) 100 mg of the crystal form A prepared in Example 2 was weighed and added into a 2 mL glass bottle. 0.5 mL of 1,4-dioxane was added, and the mixture was suspended and stirred overnight. The mixture was centrifuged to obtain a solid. The solid was dried under vacuum at room temperature for 2 h. According to the X-ray powder diffraction pattern, it is confirmed that the crystal form D was obtained.
Example 8: Preparation of Crystal Form E of D-Glucuronate of the Compound Represented by Formula (II)
(20) 100 mg of the crystal form A prepared in Example 2 was weighed and added into a 2 mL glass bottle. 0.5 mL of toluene was added, and the mixture was suspended and stirred overnight. The mixture was centrifuged to obtain a solid. The solid was dried under vacuum at room temperature for 2 h. According to the X-ray powder diffraction pattern shown in
Example 9: Preparation of Crystal Form F of D-Glucuronate of the Compound Represented by Formula (II)
(21) 100 mg of the crystal form A prepared in Example 2 was weighed and added into a 2 mL glass bottle. 0.5 mL of dichloromethane was added, and the mixture was suspended and stirred overnight. The mixture was centrifuged to obtain a solid. The solid was dried under vacuum at room temperature for 2 h. According to the X-ray powder diffraction pattern shown in
Example 10: Preparation of Other Salt Forms of the Compound Represented by Formula (II)
(22) Preparation of fumarate of the compound represented by formula (II): 150.5 mg of the compound represented by formula (II) and 23.7 mg of fumaric acid were weighed and added into a 5 ml glass bottle. 3 ml of acetone was added, and the mixture was stirred at 750 rpm for 3 days, and centrifuged to obtain a solid. The solid was dried under vacuum at room temperature for 2 h.
(23) Preparation of gentisate of the compound represented by formula (II): 150.8 mg of the compound represented by formula (II) and 31.7 mg of gentisic acid were weighed and added into a 5 ml glass bottle. 2 ml of ethanol was added, and the mixture was stirred at 750 rpm for 3 days, and centrifuged to obtain a solid. The solid was dried under vacuum at room temperature for 2 h.
(24) The acid addition salts, such as hydrochloride, sulfate, phosphate, acetate, lactate, maleate, succinate, L-malate, adipate, L-tartrate, hippurate, citrate, mucate, ascorbate, benzoate, nicotinate, ethanedisulfonate, oxalate, malonate, p-toluenesulfonate and 2-hydroxyl ethanesulfonate of the compound represented by formula (II) were prepared respectively in a similar manner.
Example 11: Stability Experiment of Crystal Form A of D-Glucuronate and Other Salts of Compound Represented by Formula (II)
(25) After being allowed to stand at 25° C., 60% RH (relative humidity) and unsealed conditions for 7 days, the relative purity and properties of crystal form A obtained in Example 2 did not change, showing good stability, whereas the hydrochloride of the compound represented by formula (II) degraded and the relative purity thereof decreased to 96.8% (the relative purity was calculated as: purity on day 7/purity on day 0*100%).
(26) After being allowed to stand at 80° C. and sealed conditions for 7 days, the relative purity and properties of crystal form A obtained in Example 2 did not change, showing good stability, whereas the hydrochloride of the compound represented by formula (II) degraded and the relative purity thereof decreased to 97.9%; and the maleate and citrate of the compound represented by formula (II) degraded and the relative purity both decreased to 98.5%. In addition, the stability of the crystal forms D, E, and F of D-glucuronate of the compound represented by formula (II) were tested under the same conditions. The results show that these three crystal forms have good stability. The above experiments show that D-glucuronate of the compound represented by formula (II) is more conducive to the preparation of stable crystal forms, and the obtained crystal forms have better stability than other salt forms.
Example 12: Test of Content of Related Substances
(27) Chromatographic Conditions:
(28) TABLE-US-00001 Instrument Thermo U3000 Column Welch Xtimate C18 4.6*150 mm, 3.5 μm Column 45° C. temperature Mobile phase A: Phosphate buffer solution (1.36 g of potassium dihydrogen phosphate was weighted and added into 1000 ml of water, dissolved with ultrasonic, adjusted the pH to 5.5 with 1 mol/L sodium hydroxide solution) - acetonitrile (80:20) B: Acetonitrile - methanol (90:10) Gradient Time (min) A% B procedure 0.0 95 5 2.00 95 5 25.00 70 30 35.00 40 60 40.00 40 60 40.10 95 5 45.00 95 5 Flow rate 1.0 ml/min Detector 225 nm Solvent Acetonitrile-water (1:1) Sample size 10 μl Sample 0.3 mg/ml sample solution, direct sample introduction. concentration Content of related substances at various retention time (min) of HPIC Sample source 8.20 11.34 16.86 17.26 23.02 23.90 26.30 Crystal form A (Example 2) — — 99.84 0.16 — — — Compound of formula (II) 0.28 0.11 97.12 0.18 1.09 0.18 0.39 (Preparation Example I)
16.86 min is the retention time of the compound represented by formula (II).
(29) It can be seen from the results in the above table that the purity of crystal form A prepared from the D-glucuronate of compound represented by formula (II) is significantly improved compared to that of the compound represented by formula (II), indicating that the D-glucuronate of the compound represented by formula (II) has obvious advantages over the compound represented by formula (II) in terms of purity and quality control.
Example 13: Crystallizability Experiment of the Compound Represented by Formula (II)
(30) a. Anti-Solvent Addition Method
(31) About 15 mg of the compound represented by formula (II) was weighed and added into a 5 mL vial, dissolved in a certain amount of solvent to obtain a clear solution. Then an anti-solvent was added dropwise into the clear solution and stirred until a solid was precipitated. The results are shown in the table below, and no new crystal form is found by X-ray powder diffraction.
(32) TABLE-US-00002 Solvent Anti-solvent Result Methanol Water Jelly Isopropyl acetate Jelly Methyl isobutyl ketone Jelly Toluene Jelly Tert-butyl methyl ether Jelly Ethanol n-heptane Jelly Water Amorphous Isopropyl acetate Jelly Tetrahydrofuran Water Jelly n-heptane Amorphous 2-methyl Toluene Jelly tetrahydrofuran Methyl isobutyl ketone Jelly dioxane Water Jelly Tert-butyl methyl ether Jelly Dimethyl sulfoxide Water Amorphous Isopropyl acetate Jelly Acetone Water Jelly n-heptane Jelly Dichloromethane n-heptane Jelly Toluene Jelly Isopropanol Water Amorphous Acetonitrile Water Amorphous
(33) b. Solvent Volatilization Method
(34) About 10 mg of the compound represented by formula (II) was weighed and added into a 1.5 mL vial, and 0.2-1.0 mL of solvent was added respectively to prepare a clear solution. The undissolved sample was filtered, and then the vial was placed at room temperature and sealed with a parafilm. After piercing 4 small holes, it was allowed to naturally volatilize. The resulting solid was collected and subjected to X-ray powder diffraction test. The results are shown in the following table. The jelly was obtained by the slow volatilization crystallization test.
(35) TABLE-US-00003 Solvent Result Solvent (v:v) Result Isopropanol Jelly Acetonitrile Jelly Acetone Jelly 2-butanone Jelly Dichloromethane Jelly Methanol/Methyl Jelly isobutyl ketone 1:1 Ethyl acetate Jelly Dioxane/Isopropyl Jelly acetate 1:1
(36) c. Slow Cooling Method
(37) About 10 mg of the compound represented by formula (II) was weighed and added into a 1.5 mL vial. 0.2-0.6 mL of solvent was added, and the mixture was stirred at 50° C. for 2 hours, and then filtered. The resulting filtrate was cooled from 50° C. to 5° C. at a speed of 0.1° C./min, and maintained at a constant temperature of 5° C. to precipitate a solid. The precipitated solid was collected and subjected to X-ray powder diffraction test. The results are shown in the following table, and no new crystal form is obtained by the slow cooling method.
(38) TABLE-US-00004 Solvent Result Solvent (v:v) Result Ethyl acetate Jelly Anisole Jelly Acetonitrile Jelly Ethanol/Water 1:1 Jelly 2-butanone Jelly 2-methyl Jelly tetrahydrofuran/n-heptane 1:1 Dichloromethane Jelly Acetone/Toluene 1:1 Jelly
(39) d. Suspending and Stirring Method
(40) About 10 mg of the compound represented by formula (II) was weighed and added into a 1.5 mL glass vial, and 0.2 mL of solvent was added respectively. The resulting suspension was stirred at room temperature and at 50° C. respectively for about 9 days, centrifuged to collect the solid and the X-ray powder diffraction test was performed. The results are shown in the table below, and no new crystal form is obtained in all of the suspending and stirring method.
(41) TABLE-US-00005 Stirring Stirring Solvent temperature Result Solvent (v:v) temperature Result Isopropanol 25° C. Jelly Toluene 25° C. Jelly Acetone 25° C. Jelly Ethanol/n-heptane 25° C. Jelly 1:1 Dichloromethane 25° C. Jelly Dimethyl 25° C. Jelly sulfoxide/Water 1:1 Ethyl acetate 25° C. Jelly Acetone/Water 25° C. Jelly 984:16 Acetonitrile 25° C. Jelly Acetone/Water 25° C. Jelly 95:5 2-butanone 25° C. Jelly Acetone/Water 25° C. Jelly 86:14 n-heptane 25° C. Amorphous Acetone/Water 25° C. Jelly 60:40 Anisole 25° C. Jelly Methanol/Water 25° C. Amorphous 1:1 Methyl 25° C. Jelly Acetonitrile/Water 25° C. Amorphous isobutyl 1:1 ketone Isopropyl 25° C. Amorphous Tetrahydrofuran/ 25° C. Amorphous acetate Water 1:2 Methyl 25° C. Amorphous Dimethyl 25° C. Amorphous tert-butyl sulfoxide/Water ether 1:2 Water 25° C. Amorphous Methanol/Water 50° C. Jelly 1:3 Water 50° C. Jelly Methanol/Water 50° C. Jelly 1:4 Ethyl acetate 50° C. Jelly Acetonitrile/Water 50° C. Jelly 1:3 Acetonitrile 50° C. Jelly Tetrahydrofuran/ 50° C. Jelly Water 1:4 2-butanone 50° C. Jelly Dimethyl 50° C. Jelly sulfoxide/Water 1:4 Anisole 50° C. Jelly 2-methyl 50° C. Jelly tetrahydrofuran/ Toluene 1:4 Methyl 50° C. Jelly Isopropanol/Toluene 50° C. Jelly isobutyl 1:4 ketone Isopropyl 50° C. Jelly Ethanol/n-heptane 50° C. Jelly acetate 1:4 n-heptane 50° C. Amorphous Dioxane/n-heptane 50° C. Jelly 1:4 Toluene 50° C. Jelly
(42) e. Gas-Solid Infiltration Method
(43) About 15 mg of the compound represented by formula (II) was weighed and added into a 3 mL vial. Another 20 mL vial was taken and about 3 mL of solvent was added. The 3 mL vial was opened and placed in the 20 mL vial. The 20 mL vial was sealed and allowed to stand at room temperature for 7 days. The solid was collected and subjected to the X-ray powder diffraction test. The results are shown in the following table, and no new crystal form is obtained by the gas-solid infiltration method.
(44) TABLE-US-00006 Solvent Result Isopropanol Jelly Acetone Jelly Dichloromethane Jelly Ethyl acetate Jelly Acetonitrile Jelly 2-butanone Jelly Chloroform Jelly Ethanol Jelly Tetrahydrofuran Jelly dioxane Jelly
(45) f. Gas-Liquid Infiltration Method
(46) About 15 mg of the compound represented by formula (II) was weighed and dissolved in a certain amount of solvent, placed into a 3 mL vial. Another 20 mL vial was taken and about 3 mL of anti-solvent was added. The 3 mL vial was opened and placed in the 20 mL vial. The 20 mL vial was sealed and allowed to stand at room temperature. When solid precipitation was observed, the solid was collected and subjected to the X-ray powder diffraction test. The results are shown in the following table, and no new crystal form is obtained by the gas-liquid infiltration method.
(47) TABLE-US-00007 Solvent Anti-solvent Result Methanol Water Amorphous Tetrahydrofuran Water Jelly Dimethyl Water Jelly sulfoxide Acetone Water Jelly Dichloromethane n-heptane Jelly dioxane n-heptane Jelly Chloroform n-heptane Jelly N, N-dimethyl n-heptane Jelly formamide Ethanol n-heptane Jelly Acetone Toluene Jelly Dichloromethane Toluene Jelly Isopropanol Toluene Jelly 2-methyl Toluene Jelly tetrahydrofuran Ethyl acetate Toluene Jelly
(48) g. Humidity Induction Method
(49) About 10 mg of the compound represented by formula (II) was weighed and added into a 3 mL vial. The vial was sealed with a parafilm with pierced 4 small holes, placed in a desiccator with a fixed humidity for 9 days. The solid was collected and subjected to the X-ray powder diffraction test. The results are shown in the table below, and no new crystal form is obtained by the humidity induction method.
(50) TABLE-US-00008 Humidity Result 97.30% Amorphous 75.30% Amorphous 57.00% Amorphous 43.20% Amorphous
(51) h. Temperature Cycling Method
(52) About 15 mg of the compound represented by formula (II) was weighed and added into a 3 mL vial. 0.2-1.0 mL of solvent was added, and the mixture was stirred at 50° C. for 2 hours, and then filtered. The resulting filtrate was subjected to 3 cycles of cooling and reheating. In each cycle, the temperature was reduced from 50° C. to 5° C. at a speed of 0.1° C./min, and then increased to 50° C. in 10 minutes. Then the filtrate was maintained at a constant temperature of 5° C. to precipitate a solid. The precipitated solid was collected and subjected to X-ray powder diffraction test. The results are shown in the following table, and no new crystal form is obtained by the temperature cycling method.
(53) TABLE-US-00009 Solvent Result Solvent (v:v) Result Isopropanol Jelly Tetrahydrofuran/ Amorphous Water 1:4 Water Amorphous Dimethyl Jelly sulfoxide/Water 1:4 2-butanone Jelly Methanol/Water Amorphous 1:1 Acetonitrile Jelly Acetonitrile/Water 1:1 Jelly
(54) The above results indicate that the crystal form of the compound represented by formula (II) cannot be obtained through numerous experiments.
Example 14: Crystallizability Experiment of Other Salt Forms of the Compound of Formula (II)
(55) Hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, L-malic acid, adipic acid, L-tartaric acid, hippuric acid, citric acid, mucic acid, ascorbic acid, benzoic acid, gentisic acid, nicotinic acid, ethanedisulfonic acid, oxalic acid, malonic acid, p-toluenesulfonic acid, 2-hydroxyl ethanesulfonic acid and the like were reacted with the compound of formula (II) to prepare the corresponding acid addition salts. The acid addition salts were then screened under the conditions of the above example. However, all of the tested salt forms failed to obtain a crystal form of the compound as characterized by X-ray powder diffraction. The products were mainly jellies, and no crystal was obtained.
(56) The embodiments of the present application have been described above. However, the present application is not limited to the above-mentioned embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.